Development of a Novel Nutrition-Related Multivariate Biomarker for Mild Cognitive Impairment Based on the Plasma Free Amino Acid Profile.

Nutritional epidemiology has shown the importance of protein intake for maintaining brain function in the elderly population. Mild cognitive impairment (MCI) may be associated with malnutrition, especially protein intake. We explored blood-based biomarkers linking protein nutritional status with MCI in a multicenter study. In total, 219 individuals with MCI (79.5 ± 5.7 year) from 10 institutions and 220 individuals who were cognitively normal (CN, 76.3 ± 6.6 year) in four different cities in Japan were recruited. They were divided into the training (120 MCI and 120 CN) and validation (99 MCI and 100 CN) groups. A model involving concentrations of PFAAs and albumin to discriminate MCI from CN individuals was constructed by multivariate logistic regression analysis in the training dataset, and the performance was evaluated in the validation dataset. The concentrations of some essential amino acids and albumin were significantly lower in MCI group than CN group. An index incorporating albumin and PFAA discriminated MCI from CN participants with the AUC of 0.705 (95% CI: 0.632-0.778), and the sensitivities at specificities of 90% and 60% were 25.3% and 76.8%, respectively. No significant association with BMI or APOE status was observed. This cross-sectional study suggests that the biomarker changes in MCI group may be associated with protein nutrition.

Real-world effectiveness of antipsychotic treatments in 1011 acutely hospitalized patients with schizophrenia: A one-year follow-up study.

PURPOSE: To compare the real-world effectiveness of antipsychotic treatments focusing on long-acting injectable antipsychotic medications (LAIs) and antipsychotic polytherapies except polytherapy involving clozapine (APEC) for patients with schizophrenia. METHODS: This prospective study was conducted over a 19-month period in 12 psychiatric emergency hospitals in Japan. Patients who were newly admitted to psychiatric emergency wards between September 2019 and March 2020 because of acute onset or exacerbation of Schizophrenia and Other Psychotic Disorders as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, were included. All patients were followed for one-year after discharge or until March 31, 2021. The primary outcome was the risk of treatment failure defined as psychiatric rehospitalization, discontinuation of medication, death, or continuation of hospitalization for one year. Cox proportional hazards multivariate regression was used for analyses. RESULTS: A total of 1011 patients were enrolled (women, 53.7%; mean [SD] age, 47.5 [14.8] years). During follow-up, 588 patients (58.2%) experienced treatment failure including rehospitalization (513 patients), discontinuation of medication (17 patients), death (11 patients), and continuation of hospitalization for one-year (47 patients). Switching to LAIs (hazard ratio [HR] 0.810, 95%CI 0.659-0.996) and APEC (HR 0.829, 95%CI 0.695-0.990) were significantly associated with a low rate of treatment failure. CONCLUSIONS: Switching to LAIs and APEC in early non-responders seems to be beneficial for the prevention of treatment failure in acutely admitted patients with schizophrenia. The risk of treatment failure was about 19% and 17% lower in patients treated with LAIs and APEC, respectively, than in patients treated without them.

Decreased circulating branched-chain amino acids are associated with development of Alzheimer's disease in elderly individuals with mild cognitive impairment.

Background: Nutritional epidemiology has shown that inadequate dietary protein intake is associated with poor brain function in the elderly population. The plasma free amino acid (PFAA) profile reflects nutritional status and may have the potential to predict future changes in cognitive function. Here, we report the results of a 2-year interim analysis of a 3-year longitudinal study following mild cognitive impairment (MCI) participants. Method: In a multicenter prospective cohort design, MCI participants were recruited, and fasting plasma samples were collected. Based on clinical assessment of cognitive function up to 2 years after blood collection, MCI participants were divided into two groups: remained with MCI or reverted to cognitively normal ("MCI-stable," N = 87) and converted to Alzheimer's disease (AD) ("AD-convert," N = 68). The baseline PFAA profile was compared between the two groups. Stratified analysis based on apolipoprotein E ε4 (APOE ε4) allele possession was also conducted. Results: Plasma concentrations of all nine essential amino acids (EAAs) were lower in the AD-convert group. Among EAAs, three branched-chain amino acids (BCAAs), valine, leucine and isoleucine, and histidine (His) exhibited significant differences even in the logistic regression model adjusted for potential confounding factors such as age, sex, body mass index (BMI), and APOE ε4 possession (p < 0.05). In the stratified analysis, differences in plasma concentrations of these four EAAs were more pronounced in the APOE ε4-negative group. Conclusion: The PFAA profile, especially decreases in BCAAs and His, is associated with development of AD in MCI participants, and the difference was larger in the APOE ε4-negative population, suggesting that the PFAA profile is an independent risk indicator for AD development. Measuring the PFAA profile may have importance in assessing the risk of AD conversion in the MCI population, possibly reflecting nutritional status. Clinical trial registration: [https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000025322], identifier [UMIN000021965].

Real-world effectiveness of antipsychotic monotherapy and polytherapy in 1543 patients with acute-phase schizophrenia.

PURPOSE: The effectiveness of antipsychotic treatments in the acute phase of schizophrenia in actual clinical practice remains somewhat unclear. Therefore, the purpose of the present naturalistic, multi-center study conducted from 1 year starting in September 2017 was to examine the response rate to an initial or second antipsychotic in newly admitted patients with acute-phase schizophrenia, as well as the response rate and quality of augmentation with two antipsychotics in patients who failed to respond to both the initial and second antipsychotics. RESULTS: In total, there were 660 (42.8%) and 243 (15.7%) responders to an initial and a second antipsychotic, respectively; thus, 58.5% of all patients were responders to an initial or second antipsychotic. Among 581 nonresponders (37.7%), the initial antipsychotic or a third antipsychotic was added to the second antipsychotic. Among these patients, 89.8% showed a Clinical Global Impression-Improvement score ≤3 (from 'minimally improved' to 'very much improved'). The rates of adverse events such as hyperglycemia, hyper-low-density lipoprotein cholesterolemia, hypertriglyceridemia, hyperprolactinemia, QTc prolongation, and extrapyramidal symptoms were not high in patients receiving augmentation with two antipsychotics compared with all patients, and no serious adverse events were reported. CONCLUSION: Antipsychotic augmentation may be an option in acute-phase treatment for patients who do not respond to either an initial or a second antipsychotic.

A prospective naturalistic multicenter study on choice of parenteral medication in psychiatric emergency settings in Japan.

AIM: To provide information about psychiatric emergency situations in Japan, we examined psychiatrists' preference among parenteral medication since intramuscular (IM)-olanzapine became available and clinical characteristics in patients given IM-olanzapine compared to those given other parenteral medication. METHODS: We conducted a naturalistic study proceeding over a 1-year period in 9 psychiatric emergency departments. RESULTS: Among 197 patients, the distribution of IM-injections (n = 89) was as follows: IM-olanzapine, 66 patients (74.2%), IM-levomepromazine, 17 patients (19.1%), IM-haloperidol, 5 patients (5.6%), and IM-diazepam, 1 patient (1.1%). The distribution of intravenous (IV)-injections (n = 108) was as follows: IV-haloperidol, 78 patients (72.2%), and IV-benzodiazepines (diazepam, flunitrazepam, or midazolam), 30 patients (27.8%). Advantages of IM-olanzapine over other parenteral medications in efficacy were found as follows: less frequent needs of an additional injection despite no difference in duration until a patient became cooperative for oral administration, and less frequent needs of restraint after the injection. Furthermore, advantages of IM-olanzapine over other injections in safety were found as follows: less frequent appearance of extrapyramidal symptoms, no occurrence of ECG abnormality and other serious adverse events except a fall, less frequent needs of an adjunctive anticholinergic drug, and less frequent needs of another kind of drug additionally injected. CONCLUSIONS: Olanzapine has rapidly become the first choice of intramuscular medication in psychiatric emergency situations since it became available in Japan, probably due to the advantages in both efficacy and safety. This study reflecting psychiatric emergency practice in Japan may contribute to periodic international comparison of psychiatric emergency practice.

Inter- and intra-observer reproducibility of quantitative analysis for FP-CIT SPECT in patients with DLB.

BACKGROUND: Dopamine transporter single photon emission CT (DAT-SPECT) is useful in the evaluation of dementia with Lewy bodies (DLB). The specific binding ratio (SBR) is an index to measure DAT density. However, poorly reproducible cases are occasionally experienced in clinical practice. We hypothesized that distance-weighted histogram (DWH) may be useful to improve the reproducibility of SBR. The purpose of this study was to investigate inter- and intra-observer reproducibility of SBR with conventional and DWH methods, and to visually evaluate the precision in reference voxel of interest (VOI) definition using these methods. METHODS: This study included 50 adult patients with probable DLB. They underwent brain MRI, DAT-SPECT, and cerebral blood flow SPECT with N-isopropyl-p-[123I]iodoamphetamine (I-123 IMP). SBR of the striatum was calculated using conventional and DWH method. For inter-observer reproducibility validation, conventional and DWH SBR were independently evaluated by experienced nuclear medicine physicians; these measurements were repeated by the nuclear medicine physician to investigate intra-observer reproducibility. RESULTS: Proper reference VOI definition was achieved in 60.0% using conventional SBR and in 98.0% with DWH SBR. Both conventional and DWH SBR demonstrated good inter- and intra-observer reproducibility, however, there were statistically significant inter- and intra-observer variations with conventional SBR measurements. Average inter- and intra-observer errors of conventional SBR were 7.9 and 6.1%, respectively. Conversely, DWH SBR errors were not observed in all patients. Moreover, average inter- and intra-observer errors were significantly higher in conventional SBR with improper reference VOI definition than in that with proper reference VOI definition. CONCLUSIONS: Although the reproducibility of conventional and DWH SBR was good, inter- and intra-observer bias could not be ignored in conventional SBR, particularly with improper reference VOI definition. Thus, DWH may be useful to improve inter- and intra-observer reproducibility of SBR.

Association of premorbid personality with behavioral and psychological symptoms in dementia with Lewy bodies: Comparison with Alzheimer's disease patients.

AIM: The aim of this study was to elucidate the relation between premorbid personality traits and behavioral and psychological symptoms in dementia (BPSD) in dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) patients. METHODS: Forty-one DLB patients and 98 AD patients were assessed for BPSD using the Neuropsychiatric Inventory (NPI). Each patient's midlife personality traits were rated by a family member using the NEO Five-Factor Inventory (NEO-FFI) questionnaire. RESULTS: In multiple regression analyses for DLB patients, NPI total score and anxiety were significantly associated with premorbid openness, delusion with premorbid agreeableness, and agitation with premorbid conscientiousness. In AD patients, depression was significantly associated with premorbid neuroticism, and agitation, apathy, and irritability with premorbid agreeableness. CONCLUSION: Premorbid personalities affected BPSD differently in DLB and AD. Given the differences in the effects of premorbid personalities on BPSD, additional studies are needed to develop interventions to reduce these symptoms.

Antipsychotic switching versus augmentation among early non-responders to risperidone or olanzapine in acute-phase schizophrenia.

PURPOSE: We examined whether augmentation with olanzapine would be superior to switching to olanzapine among early non-responders (ENRs) to risperidone, and whether augmentation with risperidone would be superior to switching to risperidone among ENRs to olanzapine. We performed a rater-blinded, randomized clinical trial at psychiatric emergency sites. Eligible patients were newly admitted patients with acute schizophrenia. ENRs to the initial antipsychotic (Clinical Global Impressions-Improvement Scale: ≥ 4 at 2 weeks) were allocated to receive either augmentation with or switching to the other antipsychotic (RIS+OLZ vs. RIS-OLZ; OLZ+RIS vs. OLZ-RIS) RESULTS: Sixty patients who completed 2 weeks of risperidone treatment were divided into 33 early responders (RIS-ER) and 27 ENRs (RIS+OLZ, n=14; RIS-OLZ, n=13). Although time to treatment discontinuation for any cause was significantly shorter in RIS+OLZ group (54.1 days [95% confidence interval, 41.3-67.0]) than in RIS-ER group (68.7 [61.2-76.2]; P=0.050), it was not significantly shorter in RIS-OLZ group (58.5 [43.1-73.9]) than in RIS-ER group (P=0.19). Sixty patients who completed 2 weeks of olanzapine treatment were divided into 36 early responders (OLZ-ER) and 24 ENRs (OLZ+RIS, n=11; OLZ-RIS, n=13). Although time to treatment discontinuation for any cause was significantly shorter in OLZ-RIS group (56.1days [40.7-71.5]) than in OLZ-ER group (74.9 [68.5-81.3]; P=0.008), it was not significantly shorter in OLZ+RIS group (64.6 [49.6-79.6]) than in OLZ-ER group (P=0.20). CONCLUSION: Despite the lack of pharmacokinetic investigation of dose adequacy in this study, it is possible that switching to olanzapine among ENRs to risperidone might have a small advantage over augmentation with olanzapine, while augmentation with risperidone might have a small advantage over switching to risperidone among ENRs to olanzapine. Further research is required before it would be appropriate to modify routine practice in the direction of these findings.

The possibility that requiring high-dose olanzapine cannot be explained by pharmacokinetics in the treatment of acute-phase schizophrenia.

We examined clinical characteristics including serum olanzapine concentrations for acute schizophrenia patients who required above conventional doses. We performed a rater-blinded, randomized clinical trial in 12 psychiatric emergency sites. Eligible patients were 18-64 years old and met diagnostic criteria for schizophrenia, acute schizophrenia-like psychotic disorder, or schizoaffective disorder. A total of 42 patients were randomly assigned by means of sealed envelopes to receive risperidone (3-12 mg/day; n=20) and olanzapine (10-40 mg/day; n=22), with follow-up at 8 weeks. The Negative score of the Positive and Negative Syndrome Scale was significantly higher in patients who required high doses than in patients who responded to conventional doses. Serum olanzapine concentrations at the time of oral 20mg/day could be obtained from 5 out of 7 patients who subsequently required high-dose olanzapine. All values were more than 30 ng/mL after 11-16 h from dosing to sample collection, and the mean value was 47.876 (S.D. 21.546) ng/mL. Such concentrations are appropriate with respect to a therapeutic range of 20-50 ng/mL. The present study has shown evidence that the reason for requiring high-dose olanzapine cannot be explained by pharmacokinetics in the treatment of acute-phase schizophrenia.

A comparison between augmentation with olanzapine and increased risperidone dose in acute schizophrenia patients showing early non-response to risperidone.

We examined whether augmentation with olanzapine would be superior to increased risperidone dose among acute schizophrenia patients showing early non-response to risperidone. We performed a rater-blinded, randomized controlled trial at psychiatric emergency sites. Eligible patients were newly admitted patients with acute schizophrenia. Early response was defined as Clinical Global Impressions-Improvement Scale score ≤3 following 2 weeks of treatment. Early non-responders were allocated to receive either augmentation with olanzapine (RIS+OLZ group) or increased risperidone dose (RIS+RIS group). The 78 patients who completed 2 weeks of treatment were divided into 52 early responders to risperidone and 26 early non-responders to risperidone (RIS+OLZ group, n=13; RIS+RIS group, n=13). No difference in the achievement of ≥50% improvement in Positive and Negative Syndrome Scale total score was observed between RIS+OLZ and RIS+RIS groups. Although time to treatment discontinuation for any cause was significantly shorter in the RIS+RIS group (6.8 weeks [95% confidence interval, 5.2-8.4]) than in early responders to risperidone (8.6 weeks [7.9-9.3]; P=0.018), there was no significant difference between the RIS+OLZ group (7.9 weeks [6.3-9.5]) and early responders to risperidone. Secondary outcomes justify the inclusion of augmentation arms in additional, larger studies comparing strategies for early non-responders.